Cardiomyocyte death has been identified in many clinically important cardiac conditions including heart failure, ischemic injury, and ventricular remodeling after infarction. Acute and chronic expression of IGF-I is cardioprotective in models of acute cardiac injury and chronic remodeling. In contrast, while acute activation of the downstream kinase, Akt, is also cardioprotective and thought to mediate many effects of IGF-I, our preliminary data suggest that chronic activation of Akt has deleterious effects associated with feedback inhibition of the signaling molecules IRS-1 and PI 3-kinase (PI3K). These studies suggest that in the absence of PI3K activation, Akt is not sufficient for cardioprotection due to loss of other critical downstream signals. The overall goals of the current proposal are to identify and define the role of Akt-independent cardioprotective mechanisms activated by IGF-I in acute ischemic injury and ventricular remodeling after infarction. This proposal is based on 3 hypotheses: 1) that chronic Akt activation leads to feedback inhibition of IRS-1 and PI3K that contributes to adverse outcomes seen in this setting; 2) that distinct, PI3K-dependent signaling pathways are necessary for full cardioprotection; and 3) that common signaling pathways also modulate ventricular remodeling after infarction. To test these hypotheses, cardiac expression of IGF-I, as well as mutant and wild-type downstream signaling molecules, will be achieved through somatic and germline gene transfer in models of cardiomyocyte death, ischemic injury, and ventricular remodeling. In Specific Aim 1, we will test the hypothesis that feedback inhibition of IRS-1/PI3K accounts for the deleterious effects of chronic Akt activation. In Specific Aim 2, we will identify the Akt-independent mechanisms of cardioprotection responsible for the benefits of IGF-I expression on cardiomyocyte survival and function in vitro and in vivo. In Specific Aim 3, we will test the hypothesis that these pathways also modulate ventricular remodeling after infarction. In Specific Aim 4, we will examine whether gene transfer of optimized cardioprotective effectors can mitigate adverse ventricular remodeling after infarction. Understanding the role of specific pathways in cardiomyocyte survival and learning to locally manipulate these pathways through gene transfer may provide novel therapeutic approaches for the management of acute ischemic injury and ventricular remodeling after infarction.